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1. Ultrasound Obstet Gynecol 2021; 58: 546–552
Published online 6 September 2021 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.23668
ASPRE trial: risk factors for development of preterm
pre-eclampsia despite aspirin prophylaxis
L. SHEN1,2
, R. J. MARTINEZ-PORTILLA3,4,5
, D. L. ROLNIK6
and L. C. POON1
1
Department of Obstetrics and Gynaecology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR,
China; 2
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; 3
Clinical
Research Division, National Institute of Perinatology ‘‘Isidro Espinosa de lo Reyes’’, Mexico City, Mexico; 4
Iberoamerican Research
Network in Obstetrics, Gynecology and Translational Medicine, Mexico City, Mexico; 5Fetal Medicine Research Center, BCNatal,
Barcelona Center for Maternal–Fetal and Neonatal Medicine (Hospital Clı́nic and Hospital Sant Joan de Deu), Institut Clı́nic de
Ginecologia, Obstetricia i Neonatologia, Universitat de Barcelona, Barcelona, Spain; 6Department of Obstetrics and Gynaecology, Monash
University, Melbourne, VIC, Australia
KEYWORDS: aspirin prophylaxis; first-trimester screening; placental growth factor; pre-eclampsia; prevention; risk factors;
uterine artery pulsatility index
CONTRIBUTION
What are the novel findings of this work?
In pregnancies at high risk of preterm pre-eclampsia, a
very high-risk result according to The Fetal Medicine
Foundation algorithm (estimated risk ≥ 1 in 50),
compared to an estimated risk of 1 in 51 to 1 in 100,
and low placental growth factor (PlGF) concentration
< 0.712 multiples of the median (MoM), compared to
PlGF ≥ 0.712 MoM, are associated with development
of preterm pre-eclampsia with delivery at < 37 weeks’
gestation despite aspirin prophylaxis.
What are the clinical implications of this work?
Our findings have clarified which patients identified as
being at high risk of preterm pre-eclampsia require closer
monitoring during pregnancy despite aspirin prophylaxis.
Women with identified risk factors should be informed
of the potential risk of developing preterm pre-eclampsia
despite aspirin use and offered more frequent monitoring
of blood pressure.
ABSTRACT
Objective To examine the possible risk factors amongst
maternal characteristics, medical and obstetric history,
pre-eclampsia (PE)-specific biomarkers and estimated-risk
group, according to The Fetal Medicine Foundation (FMF)
algorithm, that are associated with the development of
preterm PE with delivery at < 37 weeks’ gestation despite
aspirin prophylaxis.
Correspondence to: Prof. L. C. Poon, Department of Obstetrics and Gynaecology, Prince of Wales Hospital, The Chinese University of
Hong Kong, Shatin, Hong Kong SAR, China (e-mail: liona.poon@cuhk.edu.hk)
Accepted: 28 April 2021
Methods This was a secondary analysis of data from the
ASPRE trial. The study population consisted of women
with singleton pregnancy who were deemed to be at high
risk for preterm PE, based on the FMF algorithm that
combines maternal factors, mean arterial pressure, uterine
artery pulsatility index, serum pregnancy-associated
plasma protein-A and placental growth factor (PlGF)
at 11–13 weeks’ gestation. High-risk women were
randomized to receive aspirin (150 mg/day) vs placebo
from 11–14 until 36 weeks’ gestation. The primary
outcome was PE with delivery at < 37 weeks’ gestation
(preterm PE). Multivariate logistic regression analysis was
performed to identify independent predictors of preterm
PE after adjusting for the use of aspirin and other
covariates.
Results Among 1592 high-risk women, the incidence of
preterm PE was 3.0% (n = 48). The interaction between
aspirin usage and history of chronic hypertension was
significant in the prediction of preterm PE (P = 0.042),
which indicated that there was no treatment effect in
high-risk women who had chronic hypertension compared
with those who did not. Adjusting for aspirin use, the
interaction between aspirin and chronic hypertension
and other covariates, independent predictors for the
development of preterm PE were PlGF multiples of
the median (MoM) (adjusted odds ratio (aOR), 0.226
(95% CI, 0.070–0.723)) and estimated-risk group based
on the FMF algorithm. Compared to women with an
estimated risk of 1 in 51 to 1 in 100, those with an
estimated risk of 1 in 2 to 1 in 10 had a 7-fold higher
© 2021 International Society of Ultrasound in Obstetrics and Gynecology. ORIGINAL PAPER

2. Risk factors for preterm pre-eclampsia following aspirin 547
risk of developing preterm PE (aOR, 6.706 (95% CI,
2.381–18.883)), and those with an estimated risk of 1
in 11 to 1 in 50 had a 3-fold higher risk of preterm
PE (aOR, 2.769 (95% CI, 1.105–6.939)). PlGF MoM
was an independent predictor for preterm PE among
women with an estimated risk of 1 in 2 to 1 in 10
(aOR, 0.055 (95% CI, 0.005–0.668)). Among women
with an estimated risk of 1 in 11 to 1 in 100, the use
of aspirin was an independent predictor of preterm PE
(aOR, 0.276 (95% CI, 0.111–0.689)). The cut-off for
PlGF with the best performance for the prediction of
preterm PE was 0.712 MoM, with an aOR of 3.677
(95% CI, 1.526–8.862).
Conclusion In pregnancies at high risk of preterm PE
identified by screening at 11–13 weeks’ gestation using
the FMF algorithm, a very high-risk result (estimated
risk ≥ 1 in 50), compared to an estimated risk of 1
in 51 to 1 in 100, chronic hypertension, compared to
no chronic hypertension, and low PlGF concentration
(< 0.712 MoM), compared to PlGF ≥ 0.712 MoM, were
associated with the development of preterm PE despite
aspirin prophylaxis. © 2021 International Society of
Ultrasound in Obstetrics and Gynecology.
INTRODUCTION
In the Combined Multimarker Screening and Random-
ized Patient Treatment with Aspirin for Evidence-Based
Pre-eclampsia Prevention (ASPRE) trial1
, women with
singleton pregnancy identified as being at high risk
of preterm pre-eclampsia (PE) were randomized to
receive aspirin (150 mg/day) vs placebo from 11–14
until 36 weeks’ gestation. The risk for PE was deter-
mined by means of an algorithm that combines maternal
characteristics, medical and obstetric history, mean arte-
rial pressure (MAP), uterine artery pulsatility index (PI),
serum pregnancy-associated plasma protein-A (PAPP-A)
and placental growth factor (PlGF) at 11–13 weeks’
gestation2
. In the aspirin group, the incidence of preterm
PE with delivery at < 37 weeks’ gestation, which was the
primary outcome, was reduced by 62% compared with
that in the placebo group. Consequently, aspirin is an
effective agent for reduction of the incidence of preterm
PE, but a proportion of high-risk women do develop
preterm PE despite the use of aspirin. A secondary analy-
sis of the ASPRE trial has indicated that prophylactic use
of aspirin may not be useful in the prevention of preterm
PE in high-risk women with chronic hypertension3. More-
over, the benefit of aspirin in the prevention of preterm
PE appears to depend on compliance4
.
This study sought to identify the risk factors amongst
the maternal characteristics, medical and obstetric
history, PE-specific biomarkers and estimated-risk groups,
determined according to The Fetal Medicine Foundation
(FMF) algorithm, that were associated with subsequent
development of preterm PE with delivery at < 37 weeks
despite aspirin prophylaxis.
METHODS
Study design and participants
This was a secondary analysis of a prospective multicenter
study in singleton pregnancies at 11 + 0 to 13 + 6 weeks’
gestation in women attending for routine pregnancy
care at 13 maternity hospitals in the UK, Spain, Italy,
Belgium, Greece and Israel1,5
. Approval for the trial was
obtained from each individual research ethics committee
and competent authority in every country in which
the trial was conducted. Quality control of screening
and monitoring and verification were performed by the
University College London Comprehensive Clinical Trials
Unit, London, UK.
The study population consisted of participants recruited
during the second phase of the ASPRE study: the high-risk
group (calculated risk between 1 in 2 and 1 in 100
for preterm PE) that was invited to participate in a
randomized control trial (RCT) of aspirin vs placebo1
.
Criteria for eligibility were maternal age ≥ 18 years, no
serious mental illness or learning difficulty, and singleton
pregnancy with live fetus with no major abnormality
demonstrated on the 11–13-week scan. During the second
phase, 25 798 women were screened, 1592 were at high
risk for preterm PE and 48 (3.02%) developed preterm
PE with delivery at < 37 weeks.
FMF test
The FMF test was the previously reported algorithm
for first-trimester assessment of risk for preterm PE by
maternal characteristics, medical and obstetric history,
MAP, uterine artery PI, PAPP-A and PlGF6,7
. Maternal
factors were recorded8
, MAP was measured by val-
idated automated devices and standardized protocol9
,
transabdominal pulsed Doppler ultrasound was used to
measure left and right uterine artery PI and the average
PI was recorded10
. Serum PlGF and PAPP-A concentra-
tions were measured by an automated device (PAPP-A
and PlGF 1-2-3™ kits, DELFIA® Xpress random access
platform; PerkinElmer Inc., Wallac Oy, Turku, Finland).
All operators performing Doppler ultrasound evaluation
had received the appropriate Certificate of Competence
from the FMF. Measured values of MAP, uterine artery
PI, PAPP-A and PlGF were expressed as multiples of the
median (MoM); adjusting for those characteristics was
found to provide a substantive contribution to the log10
transformed value including the maternal factors in the
prior model11–14
. Gestational age was determined from
the measurement of fetal crown–rump length15
.
Outcome measure
The main outcome was PE with delivery at < 37 weeks’
gestation (referred to as preterm PE for brevity), which
was defined based on the International Society for the
Study of Hypertension in Pregnancy criteria16
. Criteria for
PE include systolic blood pressure ≥ 140 mmHg and/or
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3. 548 Shen et al.
diastolic blood pressure ≥ 90 mmHg on at least two occa-
sions, 4 h apart, developing after 20 weeks of gestation
in previously normotensive women. Hypertension must
be accompanied by proteinuria of ≥ 300 mg in 24 h or
two readings of at least 2+ on dipstick analysis of mid-
stream or catheter urine specimens if no 24-h collection
is available. In PE superimposed on chronic hypertension,
significant proteinuria (as defined above) should develop
after 20 weeks of gestation in women with known chronic
hypertension (history of hypertension before conception
or the presence of hypertension before 20 weeks’ gestation
in the absence of trophoblastic disease).
Data on pregnancy outcome, risk calculations and
maternal history were collected from the hospital
maternity records. The obstetric records of all women
with pre-existing or pregnancy-associated hypertension
were examined to determine if the condition was PE
before inclusion in the database. Drug compliance was
reported as the tablet count percentage difference of the
total number of tablets consumed against the total number
of tablets prescribed.
Statistical analysis
Quantitative variables were assessed for normality
using the Shapiro–Wilk test. Normally distributed
variables were compared using the one-way ANOVA test
and expressed as mean ± SD. Non-normally distributed
variables were compared using the Kruskal–Wallis test
and expressed as median and interquartile range (IQR).
Qualitative variables were compared using the χ2
or
Fisher’s exact test.
The study population was divided according to their
estimated risk of preterm PE according to the FMF algo-
rithm into the following groups: risk of 1 in 2 to 1 in 10;
risk of 1 in 11 to 1 in 50; and risk of 1 in 51 to 1 in 100.
Multivariate regression analysis was used to determine
which of the factors amongst maternal characteristics,
medical and obstetric history, PE-specific biomarkers
and estimated-risk groups were significant predictors of
preterm PE. In the subgroups of women with an esti-
mated risk of 1 in 2 to 1 in 10 and 1 in 11 to 1 in 100,
multivariate regression analysis was used to determine
which of the factors amongst maternal characteristics,
medical and obstetric history and PE-specific biomarkers
were significant predictors of preterm PE. The stepwise
regression comprised the following predictors: aspirin;
chronic hypertension; interaction between aspirin and
chronic hypertension; age; race; height; weight; concep-
tion type; smoking status; systemic lupus erythematosus;
diabetes; previous PE; family history of PE; MAP MoM;
uterine artery MoM; PlGF MoM; and compliance to
aspirin. For the development of prediction models, we
used forward and backward stepwise logistic regression
analysis, in which a P-value of 0.06 was used for variable
inclusion and a P-value of 0.05 was used for variable
elimination, forcing the use of aspirin and the inter-
action between aspirin usage and chronic hypertension
as part of the models. Variance inflation factor (VIF),
which represents the factor by which the variance is
inflated, was used to assess multicollinearity; VIF > 4
required further investigation, whereas VIF > 10, which
was considered a sign of serious multicollinearity, required
correction. To determine the best cut-off point of PlGF
MoM for the prediction of preterm PE, non-parametric
receiver-operating-characteristics-curve analysis was per-
formed, and the cut-off point was selected using the best
likelihood for the given outcome of preterm PE. Data were
analyzed using STATA for Mac, v.14.1 (STATA Corp.,
College Station, TX, USA).
RESULTS
The characteristics of the study population according
to the estimated risk for preterm PE, as determined by
the FMF algorithm, are provided in Table 1. The rate of
aspirin compliance was not significantly different between
the three groups (P = 0.340).
The interaction between aspirin usage and history
of chronic hypertension was significant for the predic-
tion of preterm PE (P = 0.042; Table 2). High-risk women
with chronic hypertension who were treated with aspirin
had an increased risk of preterm PE, while the use of
aspirin in women without chronic hypertension was
associated with a significant reduction in the risk of
preterm PE.
Maternal age and MAP MoM had VIFs of 14.31
and 40.96, respectively, indicating high multicollinearity
and were removed sequentially from the multivariate
regression analysis. In the final multivariate model,
aspirin usage, the interaction between aspirin and chronic
hypertension, PlGF MoM and estimated-risk group were
significant independent predictors of preterm PE (Table 2).
PlGF MoM had a VIF of 4.63, which was investigated
by testing for an interaction between PlGF MoM, aspirin
usage and chronic hypertension, but no significant results
were identified (P = 0.369).
Compared to women with an estimated risk of 1 in
51 to 1 in 100 based on FMF algorithm, women with an
estimated risk of 1 in 2 to 1 in 10 had a 7-fold higher risk of
developing preterm PE (adjusted odds ratio (aOR), 6.706
(95% CI, 2.381–18.883), while those with an estimated
risk of 1 in 11 to 1 in 50 showed a 3-fold higher risk
of preterm PE (aOR, 2.769 (95% CI, 1.105–6.939)).
VIF analysis showed an adequate fitting of the final
model (mean VIF, 1.86) with all predictors having a
VIF < 2.24.
Amongst women with an estimated risk of 1 in 2
to 1 in 10 based on the FMF algorithm, only PlGF
MoM (aOR, 0.055 (95% CI, 0.005–0.668)) was found
to be an independent predictor of preterm PE (Table 3),
while in women with an estimated risk of 1 in 11 to 1
in 100, aspirin usage was the only independent predic-
tor of preterm PE (aOR, 0.276 (95% CI, 0.111–0.689);
Table 4). The cut-off for PlGF with the best perfor-
mance for the prediction of preterm PE was 0.712 MoM,
with an aOR of 3.677 (95% CI, 1.526–8.862)
(Table 5).
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4. Risk factors for preterm pre-eclampsia following aspirin 549
Table 1 Characteristics of women with singleton pregnancy at high risk of preterm pre-eclampsia (PE), as determined by The Fetal Medicine
Foundation algorithm, according to risk group
Characteristic
Total
(n = 1592)
1 in 2 to 1 in 10
(n = 184)
1 in 11 to 1 in 50
(n = 767)
1 in 51 to 1 in 100
(n = 641) P
Age (years) 31.4 (27.12–35.72) 32.68 (27.91–37.05) 31.29 (27.04–35.51) 31.24 (27.08–35.53) 0.021
Racial origin < 0.001
White 1073 (67.40) 103 (55.98) 492 (64.15) 478 (74.57)
Black 398 (25.00) 64 (34.78) 212 (27.64) 122 (19.03)
South Asian 73 (4.59) 10 (5.43) 41 (5.35) 22 (3.43)
East Asian 29 (1.82) 5 (2.72) 12 (1.56) 12 (1.87)
Mixed 19 (1.19) 2 (1.09) 10 (1.30) 7 (1.09)
Height (cm) 163 (159–167.5) 163 (159–167) 163 (159–167) 164 (159–168) 0.217
Weight (kg) 70.4 (61.5–83.6) 70.4 (59.3–86.6) 70.4 (61.7–84.8) 70.5 (61.0–81.4) 0.598
Conception 0.452
Spontaneous 1500 (94.22) 175 (95.11) 718 (93.61) 607 (94.70)
Ovulation drugs 13 (0.82) 3 (1.63) 6 (0.78) 4 (0.62)
In-vitro fertilization 79 (4.96) 6 (3.26) 43 (5.61) 30 (4.68)
Smoker 114 (7.16) 15 (8.15) 55 (7.17) 44 (6.86) 0.837
Systemic lupus erythematosus 4 (0.25) 1 (0.54) 0 (0) 3 (0.47) 0.153
Antiphospholipid syndrome 4 (0.25) 0 (0) 1 (0.13) 3 (0.47) 0.348
Pre-existing diabetes 0.411
No previous diabetes 1568 (98.49) 179 (97.28) 754 (98.31) 635 (99.06)
Type-1 diabetes 9 (0.57) 2 (1.09) 4 (0.52) 3 (0.47)
Type-2 diabetes 15 (0.94) 3 (1.63) 9 (1.17) 3 (0.47)
Chronic hypertension 107 (6.72) 47 (25.54) 51 (6.65) 9 (1.40) < 0.001
Obstetric history < 0.001
Nulliparous 1072 (67.34) 100 (54.35) 514 (67.01) 458 (71.45)
Parous without previous PE 350 (21.98) 44 (23.91) 166 (21.64) 140 (21.84)
Parous with previous PE 170 (10.68) 40 (21.74) 87 (11.34) 43 (6.71)
Family history of PE 0.009
No family history of PE 1430 (89.82) 154 (83.70) 685 (89.31) 591 (92.20)
Mother with PE 138 (8.67) 27 (14.67) 71 (9.26) 40 (6.24)
Sister with PE 24 (1.51) 3 (1.63) 11 (1.43) 10 (1.56)
Mean arterial pressure MoM 1.08 (1.02–1.14) 1.12 (1.05–1.58) 1.08 (1.03–1.14) 1.07 (1.01–1.12) < 0.001
Uterine artery PI MoM 1.25 (1.04–1.47) 1.36 (1.10–1.58) 1.29 (1.05–1.50) 1.20 (1.01–1.39) < 0.001
PlGF MoM 0.69 (0.51–0.92) 0.50 (0.34–0.79) 0.66 (0.49–0.88) 0.78 (0.61–0.98) < 0.001
Aspirin intake 785 (49.31) 83 (45.11) 372 (48.50) 330 (51.48) 0.258
Drug compliance (%) 95.7 (87.8–98.8) 96.1 (89.1–98.8) 95.5 (87.1–98.8) 96.1 (88.6–98.8) 0.340
Gestational age at delivery (weeks) 39.3 (38.1–40.3) 38.8 (37.1–39.9) 39.3 (38.1–40.3) 39.6 (38.4–40.4) < 0.001
Preterm PE 48 (3.02) 18 (9.78) 24 (3.13) 6 (0.94) < 0.001
Data are given as median (interquartile range) or n (%). Comparison between groups was performed using χ2 or Fisher’s exact test for
categorical variables and Kruskal–Wallis rank test for continuous variables using the Dunn’s test for post-hoc correction (critical statistical
significance, P < 0.05). MoM, multiples of the median; PI, pulsatility index; PlGF, placental growth factor.
Table 2 Multivariate prediction model of maternal factors, biomarkers and estimated-risk group for preterm pre-eclampsia with delivery at
< 37 weeks in high-risk women, according to The Fetal Medicine Foundation algorithm, following aspirin prophylaxis
Parameter aOR (95% CI) SE Coefficient SE P
Aspirin 0.276 (0.125–0.612) 0.112 −1.286564 0.405519 0.002
CH 1.697 (0.568–5.071) 0.948 0.528706 0.558621 0.344
Interaction between aspirin and CH 5.092 (1.059–24.479) 4.079 1.627711 0.801081 0.042
Placental growth factor MoM 0.226 (0.070–0.723) 0.134 −1.488066 0.593950 0.012
Estimated-risk group
1 in 51 to 1 in 100 (reference) 1
1 in 11 to 1 in 50 2.769 (1.105–6.939) 1.298 1.018590 0.468691 0.030
1 in 2 to 1 in 10 6.706 (2.381–18.883) 3.542 1.902937 0.528250 < 0.001
Constant 0.050 (0.016–0.159) 0.029 −2.995616 0.589179 < 0.001
aOR, adjusted odds ratio; CH, chronic hypertension; MoM, multiples of the median; SE, standard error.
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5. 550 Shen et al.
Table 3 Multivariate prediction model of maternal factors and biomarkers for preterm pre-eclampsia with delivery at < 37 weeks in women
with an estimated risk of 1 in 2 to 1 in 10, according to The Fetal Medicine Foundation algorithm, following aspirin prophylaxis
Parameter aOR (95% CI) SE Coefficient SE P
Aspirin 0.320 (0.062–1.643) 0.267 −1.138865 0.8343157 0.172
CH 3.932 (0.832–18.582) 3.116 1.369083 0.7924068 0.084
Interaction between aspirin and CH 4.154 (0.375–46.045) 5.098 1.424077 1.227342 0.246
Placental growth factor MoM 0.055 (0.005–0.668) 0.070 −2.89257 1.269629 0.023
Constant 0.472 (0.139–1.603) 0.294 −0.7506632 0.6237066 0.229
aOR, adjusted odds ratio; CH, chronic hypertension; MoM, multiples of the median; SE, standard error.
Table 4 Multivariate prediction model for preterm pre-eclampsia with delivery at < 37 weeks in women with an estimated risk of 1 in 11 to
1 in 100, according to The Fetal Medicine Foundation algorithm, following aspirin prophylaxis
Parameter aOR (95% CI) SE Coefficient SE P
Aspirin 0.276 (0.111–0.689) 0.129 −1.287129 0.4666079 0.006
CH 1.009 (0.131–7.781) 1.051 0.0087797 1.042307 0.993
Interaction between aspirin and CH 8.891 (0.641–123.322) 11.930 2.185072 1.341721 0.103
Constant 0.037 (0.024–0.057) 0.008 −3.304616 0.2221875 < 0.001
aOR, adjusted odds ratio; CH, chronic hypertension; SE, standard error.
Table 5 Multivariate prediction model of maternal factors, placental growth factor (PlGF) < 0.712 multiples of the median (MoM) and
estimated-risk group for preterm pre-eclampsia with delivery at < 37 weeks in high-risk women, according to The Fetal Medicine
Foundation algorithm, following aspirin prophylaxis
Parameter aOR (95% CI) SE Coefficient SE P
Aspirin 0.290 (0.131–0.645) 0.118 −1.236319 0.407118 0.002
CH 1.494 (0.515–4.335) 0.812 0.401140 0.543644 0.461
Interaction between aspirin and CH 4.170 (0.882–19.715) 3.305 1.428003 0.792545 0.072
PlGF < 0.712 MoM 3.677 (1.526–8.862) 1.650 1.302092 0.448850 0.004
Estimated-risk group
1 in 51 to 1 in 100 (reference) 1
1 in 11 to 1 in 50 3.158 (1.270–7.848) 1.467 1.149813 0.464542 0.013
1 in 2 to 1 in 10 7.423 (2.656–20.750) 3.893 2.004613 0.524476 < 0.001
Constant 0.015 (0.007–0.035) 0.006 −4.187774 0.423908 < 0.001
aOR, adjusted odds ratio; CH, chronic hypertension; SE, standard error.
DISCUSSION
Main findings
In this study, we evaluated risk factors for development
of preterm PE following aspirin treatment in women
identified by first-trimester screening to be at high risk
of preterm PE. There are four main findings in this
study. First, in the prediction of preterm PE there
is a significant interaction between aspirin use and
history of chronic hypertension. Thus, high-risk women
with chronic hypertension treated with aspirin remain
at high risk of preterm PE, whereas aspirin usage in
women without chronic hypertension is associated with
a significant reduction in the risk of preterm PE. Second,
women with an estimated risk of 1 in 2 to 1 in 10 and
that of 1 in 11 to 1 in 50, compared to women with an
estimated risk of 1 in 51 to 1 in 100, have a 7-fold and
3-fold higher risk, respectively, of developing preterm PE.
Third, low PlGF MoM is a significant risk factor for the
development of preterm PE; the cut-off for defining low
PlGF level that is associated with subsequent development
of preterm PE is 0.712 MoM. Fourth, in women with an
estimated risk of 1 in 2 to 1 in 10, low PlGF MoM is an
independent predictor for preterm PE, whereas, in those
with an estimated risk of 1 in 11 to 1 in 100, only the use
of aspirin is an independent predictor of preterm PE.
Comparison with previous studies
In this secondary analysis of the ASPRE data, we
have found that women with an estimated risk for
preterm PE of 1 in 2 to 1 in 10 and that of 1 in 11
to 1 in 50 based on the FMF algorithm, compared to
those with an estimated risk of 1 in 51 to 1 in 100, are
more likely to develop PE despite aspirin prophylaxis.
We have suggested previously that aspirin does not
prevent but delays development of PE. In an exploratory
analysis of data from the ASPRE trial to test the
aspirin-related delay hypothesis, a reduction in the
incidence of term PE in the lower-risk group (OR,
0.62 (95% CI, 0.29–1.30)) was observed, while in the
higher-risk group there was a small increase in the
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6. Risk factors for preterm pre-eclampsia following aspirin 551
incidence of term PE (OR, 1.11 (95% CI, 0.71–1.75))17
.
Within the framework of the aspirin-related delay
hypothesis, the effect of aspirin was to delay the
gestational age at delivery with PE by an estimated 4.4
(95% CI, 1.4–7.1) weeks for those who would deliver at
24 weeks without aspirin treatment. The effect decreased
by an estimated 0.23 (95% CI, 0.021–0.40) weeks for
each week of gestation so that at 40 + 0 weeks, the
estimated delay was 0.8 (95% CI, −0.03 to 1.7) weeks.
These findings imply that the aspirin-related delay in
gestational age at delivery is greater for early-onset than
late-onset PE. Based on these findings, it is therefore highly
probable that women at a very high risk of preterm PE
can still benefit from aspirin prophylaxis and that despite
a delay in the onset of disease, delivery still occurs before
37 weeks’ gestation.
Other studies have attempted to evaluate the reasons
for the development of PE despite aspirin prophylaxis.
Block-Abraham et al.18
demonstrated, in a nested cohort
study of prospectively enrolled women with verified ini-
tiation of risk-indicated aspirin prophylaxis by 16 weeks’
gestation, that women who developed PE while taking
prophylactic aspirin were more likely to have chronic
hypertension, diabetes and obesity and had elevated
first-trimester blood pressure and lower serum PAPP-A
concentration; normotension was shown to be associ-
ated with a reduced risk of PE. The same research group
demonstrated that, in women treated with prophylac-
tic aspirin from the first trimester, those who developed
PE had significantly and sustained higher blood pressure
from the onset of pregnancy compared with those who
did not develop PE19
. Only women with an average blood
pressure below 125/75 mmHg had a PE rate resembling
that of low-risk population, suggesting that there is an
independent contribution of a woman’s gestational blood
pressure trend to developing PE, which is not mitigated by
low-dose aspirin. In our cohort, maternal weight, height
and diabetes were not associated with the development
of preterm PE despite aspirin prophylaxis. As PAPP-A
is highly correlated with PlGF, it was not assessed as a
potential predictor for the development of preterm PE20
.
Implications for clinical practice
The controversy about the role of aspirin in preventing
PE has lasted for many decades21,22
. The ASPRE trial
has proven that the administration of aspirin to women
identified as being at high risk for preterm PE can reduce
the incidence and severity of the disease1
. Nevertheless,
it is undeniable that there is still a proportion of
high-risk women who develop preterm PE despite aspirin
prophylaxis from 11 + 0 to 14 + 6 weeks’ gestation. Our
findings have shed some light on the types of patients
that require closer monitoring during pregnancy, despite
aspirin prophylaxis. Patients with very high risk for
preterm PE based on the FMF algorithm (estimated risk
≥ 1 in 50), compared to those with an estimated risk of
1 in 51 to 1 in 100, those with chronic hypertension,
compared to those without chronic hypertension, and
those with low PlGF (< 0.712 MoM), compared to those
with PlGF ≥ 0.712 MoM, should be informed of the
potential risk of developing PE despite aspirin use and
offered more frequent monitoring of blood pressure.
This could be in the form of 2–4-weekly clinical
assessments of blood pressure, depending on the observed
blood pressure measurements, together with home blood
pressure monitoring.
Strengths and limitations
The main strength of this study was that this secondary
analysis was based on well-collected data from a RCT
that evaluated aspirin vs placebo in the prevention of
preterm PE. Another strength was that the trial drug
adherence was recorded accurately and was not found to
be significantly different between the three risk groups.
However, the RCT did not have enough statistical
power for such secondary analysis as there were only
48 cases of preterm PE, which limited the number of
predictive variables included in the multivariate logistic
regression analysis. Moreover, the study was only able to
identify risk factors among maternal factors, PE-specific
biomarkers and estimated-risk group and did not allow for
an exploratory analysis of other causes of PE development
despite aspirin prophylaxis.
Conclusion
In pregnancies at high risk of preterm PE identified by
screening at 11–13 weeks’ gestation, a very high-risk
result according to the FMF algorithm (estimated risk ≥ 1
in 50), compared to an estimated risk of 1 in 51 to 1 in
100, chronic hypertension, compared to no chronic hyper-
tension, and low PlGF concentration (< 0.712 MoM),
compared to PlGF ≥ 0.712 MoM, are associated with the
development of preterm PE with delivery at < 37 weeks’
gestation despite aspirin prophylaxis.
ACKNOWLEDGMENTS
This study was supported by grants from The Fetal
Medicine Foundation (Charity No: 1037116) and
by the European Union 7th
Framework Programme
- FP7-HEALTH-2013-INNOVATION-2 (ASPRE Project
#601852). These bodies had no role in the study design,
collection, analysis and interpretation of data; in the
writing of the report; or in the decision to submit the
article for publication.
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